# US 11,110,095 B2 · Pyrimidine compounds as JAK kinase inhibitors

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- Number: US 11,110,095 B2
- Document ID: US11110095B2
- Status: Granted
- Kind: B2
- Application number: 16/656,927
- Filed: 2019-10-18
- Published: 2020-02-13
- Granted: 2021-09-07
- Earliest claimed: 2016-04-28
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Ryan Hudson; Jennifer Kozak; Melissa Fleury; Paul R. Fatheree; Anne-Marie Beausoleil; Dante D. Podesto; Xiaojun Huang
- Web page: https://patentgrep.com/patent/US11110095B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/00: Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D 211/06: having no double bonds between ring members or between ring members and non-ring members
- C07D 451/04: with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D 451/14: containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
- C07D 487/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds of formula (I): wherein the variables are defined in the specification, or a pharmaceutically-acceptable salt thereof, that are inhibitors of JAK kinases. The invention also provides pharmaceutical compositions comprising such compounds, methods of using such compounds to treat gastrointestinal and other inflammatory diseases, and processes and intermediates useful for preparing such compounds.

## Claims

### Claim 1

A method of treating a gastrointestinal inflammatory disease selected from the group consisting of collagenous colitis, lymphocytic colitis, Behcet's disease, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, Crohn's disease, celiac disease, ulcerative colitis, immune checkpoint inhibitor induced colitis and infectious colitis, in a mammal, the method comprising administering to the mammal a compound of formula (I):
wherein
R1 is selected from:
(a) —S(O)2R4, wherein R4 is selected from:
C1-4alkyl, wherein C1-4alkyl is optionally substituted with CN, —OC1-3alkyl, or C3-6cycloalkyl,
heterocyclyl containing 4 to 6 ring atoms including one nitrogen atom,
wherein any heterocyclyl is optionally substituted with CN, C3-6cycloalkyl,
pyridinyl, wherein pyridinyl is optionally substituted with fluoro, and phenyl;
(b) C1-4alkyl, wherein C1-4alkyl is optionally substituted with —CN
or
pyridinyl, wherein pyridinyl is optionally substituted with —CN; and
(c) —C(O)R5, wherein R5 is selected from:
C1-4alkyl, wherein C1-4alkyl is optionally substituted with C3-6cycloalkyl, or with one or two fluoro,
—OC1-4alkyl,
C3-6cycloalkyl, and
morpholinyl;
R2 is hydrogen or methyl;
R3 is C1-3alkyl; and
n is 1 or 2;
or a pharmaceutically-acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the method further comprises administering one or more other therapeutic agents useful for treating a gastrointestinal inflammatory disease.

### Claim 3 (depends on 1)

The method of claim 1 wherein the gastrointestinal inflammatory disease is ulcerative colitis.

### Claim 4

A method of treating an inflammatory disease of the skin in a mammal, the method comprising applying a pharmaceutical composition comprising a compound of formula (I):
wherein
R1 is selected from:
(a) —S(O)2R4, wherein R4 is selected from:
C1-4alkyl, wherein C1-4alkyl is optionally substituted with —CN, —OC1-3alkyl, or C3-6cycloalkyl,
heterocyclyl containing 4 to 6 ring atoms including one nitrogen atom,
wherein any heterocyclyl is optionally substituted with —CN, C3-6cycloalkyl,
pyridinyl, wherein pyridinyl is optionally substituted with fluoro, and phenyl;
(b) C1-4alkyl, wherein C1-4alkyl is optionally substituted with —CN
or
pyridinyl, wherein pyridinyl is optionally substituted with —CN; and
(c) —C(O)R5, wherein R5 is selected from:
C1-4alkyl, wherein C1-4alkyl is optionally substituted with C3-6cycloalkyl, or with one or two fluoro,
—OC1-4alkyl,
C3-6cycloalkyl, and
morpholinyl;
R2 is hydrogen or methyl;
R3 is C1-3alkyl; and
n is 1 or 2;
or a pharmaceutically-acceptable salt thereof to the skin of the mammal.

### Claim 5 (depends on 4)

The method of claim 4, wherein the inflammatory disease is atopic dermatitis.

### Claim 6 (depends on 4)

The method of claim 4, wherein the compound is a compound of formula:
or a pharmaceutically-acceptable salt thereof.

### Claim 7 (depends on 3)

The method of claim 3, wherein the ulcerative colitis is selected from the group consisting of proctosigmoiditis, pancolitis, ulcerative proctitis and left-sided colitis.

### Claim 8 (depends on 1)

The method of claim 1, wherein the gastrointestinal inflammatory disease is selected from the group consisting of collagenous colitis, lymphocytic colitis, Behcet's disease, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis.

### Claim 9 (depends on 1)

The method of claim 1, wherein the gastrointestinal inflammatory disease is Crohn's disease.

### Claim 10 (depends on 1)

The method of claim 1, wherein the gastrointestinal inflammatory disease is celiac disease.

### Claim 11 (depends on 1)

The method of claim 1, wherein the gastrointestinal inflammatory disease is immune checkpoint inhibitor induced colitis.

### Claim 12 (depends on 1)

The method of claim 1 wherein the mammal is a human.

### Claim 13

A method of treating a gastrointestinal inflammatory disease selected from the group consisting of collagenous colitis, lymphocytic colitis, Behcet's disease, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, Crohn's disease, celiac disease, ulcerative colitis, immune checkpoint inhibitor induced colitis and infectious colitis, in a mammal, the method comprising administering to the mammal a compound of formula:
or a pharmaceutically-acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the mammal is a human.

### Claim 15 (depends on 14)

The method of claim 14, wherein the compound is administered as a free base.

### Claim 16 (depends on 15)

The method of claim 15, wherein the compound is administered as a crystalline form of 1-(((1R,3s,5S)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methoxypyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile, wherein the crystalline form is characterized by a powder X-ray diffraction comprising diffraction peaks at 2θ values of 8.89±0.20, 12.99±0.20, 13.44±0.20, and 20.16±0.20.

### Claim 17 (depends on 16)

The method of claim 16, wherein the powder X-ray diffraction pattern is further characterized by having two or more additional diffraction peaks at 2θ values selected from 10.64±0.20, 10.99±0.20, 15.02±0.20, 15.74±0.20, 16.47±0.20, 20.93±0.20, 22.22±0.20, and 26.25±0.20.

### Claim 18 (depends on 14)

The method of claim 14, wherein the gastrointestinal inflammatory disease is ulcerative colitis.

### Claim 19 (depends on 14)

The method of claim 14, wherein the gastrointestinal inflammatory disease is Crohn's disease.

### Claim 20 (depends on 14)

The method of claim 14, wherein the gastrointestinal inflammatory disease is celiac disease.

### Claim 21 (depends on 14)

The method of claim 14, wherein the gastrointestinal inflammatory disease is immune checkpoint inhibitor induced colitis.

### Claim 22 (depends on 14)

The method of claim 14, wherein the gastrointestinal inflammatory disease is selected from the group consisting of collagenous colitis, lymphocytic colitis, Behcet's disease, ileitis, eosinophilic esophagitis, graft versus host disease-related colitis, and infectious colitis.